Cinnamic compounds and derivatives therefrom for the inhibition of histone deacetylase

Abstract

The invention relates to a compound represented by the following formula (I): and pharmaceutically acceptable salts, stereoisomers, enantiomers, prodrugs and solvates thereof. The compounds are useful as an agent for enhancing the neurite outgrowth and preventing or treating of diseases associated with HDAC in particular, tumor or cell proliferative diseases. In particular, the compounds of the invention can be used as an agent for anti-cancer, anti-diabetic, and anti-neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Spinocerebellar Ataxias (SCA), and human spinal muscular atrophy (SMA).

1. A method of inhibiting histone deacetylase (HDAC) in a subject, which comprises administering to said subject a therapeutically effective amount of a compound represented by the following formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, alkyl, alkenyl, C 3-8  cycloalkyl, 5-membered or 6-membered unsaturated carbocycle or 5-membered or 6-membered heterocycle; 
         X is CH 2 , O, NH or S; 
         Y is O, NH or O—C 1-4 -alkyl; 
         n is an integer of 0 to 10; 
         m is an integer of 1 to 5; 
         R 2  and R 3  is independently C 1-6  alkyl; 
         R 4  is C 5-6  cycloalkyl or 5-membered or 6-membered unsaturated carbocycle or heterocycle which may be substituted with halogen, CF 3 , OR 7  or NR 7 R 8 , wherein R 7  and R 8  are independently hydrogen or C 1-6  alkyl; 
         R 5  is OH, NH 2  or C 5-6  cycloalkyl, 5-membered or 6-membered unsaturated carbocycle or heterocycle wherein the cycloalkyl, carboycle and heterocycle may be optionally substituted with halogen, NH 2 , NO 2 , C 1-6  alkoxy, C 1-6  alkylthio, OR 7 , NR 7 R 8  or CF 3 , wherein R 7  and R 8  are independently hydrogen or C 1-6  alkyl; and 
         R 6  is H, C 1-10 alkyl which may be substituted by hydroxy or C 2-10 alkenyl, or together with R 1  being —C 2 H 2 —; 
         or a pharmaceutically acceptable salt, stereoisomer, or enantiomer thereof. 
       
     
     
       2. A method of treating diabetic disease in a subject, which comprises administering to said subject a therapeutically effective amount of the compound as defined in  claim 1  or pharmaceutically acceptable salt, stereoisomer or enantiomer thereof. 
     
     
       3. A method of treating tumor or cell proliferative disease in a subject, which comprises administering to said subject a therapeutically effective amount of the compound as defined in  claim 1  or a pharmaceutically acceptable salt, stereoisomer or enantiomer thereof. 
     
     
       4. A method of enhancing the neurite outgrowth in a subject, which comprises administering to said subject a therapeutically effective amount of the compound as defined in  claim 1  or a pharmaceutically acceptable salt, stereoisomer or enantiomer thereof. 
     
     
       5. A method of treating neurodegenerative diseases and human spinal muscular atrophy (SMA) disease in a subject, which comprises administering to said subject a therapeutically effective amount of the compound as defined in  claim 1  or a pharmaceutically acceptable salt, stereoisomer or enantiomer thereof. 
     
     
       6. The method of  claim 5 , wherein the neurodegenerative disease is Huntington's disease or poly-glutamine disease.